Patient‐reported physical well‐being predicts good long‐term survival of hematopoietic stem cell transplantation

Abstract Aim This study aimed to explore the association between patient‐reported items at different time points after hematopoietic stem cell transplantation (HSCT) and long‐term survival. Methods We conducted a study with 144 allogeneic HSCT patients, following them for 5 years post‐transplantation. Data from the Functional Assessment of Cancer Therapy‐Bone Marrow Transplant (FACT‐BMT) questionnaire were collected before transplantation and at 1, 3, 6, 12, 18, 36, and 60 months after transplantation. Demographic characteristics and survival status were also assessed. Results Among the 144 cases, the 5‐year overall survival (OS), progression‐free survival (PFS), non‐relapse mortality (NRM), and graft‐versus‐host disease‐free (GRFS) rates were 65%, 48%, 17%, and 36% respectively. Health‐related quality of life (HRQOL) showed a fluctuating pattern over 5 years. Using a latent class mixed model, patients were classified into two groups based on their physical well‐being (PWB) scores during the 60‐month follow‐up. Class 1 had initially lower PWB scores, which gradually increased over time. In contrast, Class 2 maintained higher PWB scores with slight increases over time. Kaplan–Meier survival analysis revealed that Class 1 had better OS (70.9% vs. 52.9%, p = 0.021), PFS (60.5% vs. 41.2%, p = 0.039), and GRFS (35.1% vs. 29.3%, p = 0.035) compared to Class 2. Conclusions Patients who had higher initial PWB scores after HSCT demonstrated improved long‐term survival outcomes. The PWB score could serve as a valuable predictor for the prognosis of HSCT.


| INTRODUCTION
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a powerful therapeutic strategy for patients diagnosed with high-risk hematologic malignancies. 1,2Annually, over 60,000 individuals worldwide undergo either allogeneic or autologous HSCT, leading to an increase in survivorship. 3owever, long-term morbidity and late mortality continue to present significant challenges. 4Therefore, the ongoing improvement and enhancement of patients' quality of life (QOL) following HSCT remain a central focus.
6][7][8] For example, the Hematopoietic Cell Transplantation-Composite Risk (HCT-CR), which incorporates the refined disease risk index (DRI-R) and the hematopoietic stem-cell transplant comorbidity/age index (HCT-CI/ Age), has been shown to more accurately predict the risk of death associated with Allo-HSCT compared to conventional models for patients diagnosed with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). 2 Despite patient-reported outcomes (PROs) being recognized as predictors of mortality in various cancer types, their consideration within the HSCT field remains limited. 9In HSCT, over 90% of survivors experience at least one severe late adverse effect resulting from the treatment. 10Consequently, thorough assessment and documentation of patients' QOL have become increasingly important in clinical management.][13][14] QOL is a comprehensive concept that can change over time based on individual assessments and environmental factors, encompassing various aspects of patients' experiences. 15,16Allo-HSCT patients typically undergo distinct treatment stages, during which their QOL may vary. 17lthough our previous research identified the trajectory of QOL in the early stages of HSCT, the long-term progression of QOL among survivors and whether early-stage QOL can effectively predict survival outcomes remain unclear.Therefore, we conducted a 5-year follow-up study with Allo-HSCT patients, examining their QOL at 12, 18, 36, and 60 months post-transplantation to determine their long-term QOL trajectories and explore the relationship between HSCT treatment efficacy and QOL.

| Participants
We conducted a retrospective analysis of patients who underwent HSCT between July 22, 2016, and April 30, 2017, at the First Affiliated Hospital of Soochow University in China.Patients were included if they were 18 years old or older and were willing to participate in the study.Patients with mental illness or cognitive impairment were excluded, as were those illness was recrudescent, who were too sick to participate, or who die.These patients had previously participated in our investigation and completed assessments before transplantation, as well as at 1, 3, and 6 months post-transplantation, totaling 191 patients were enrolled.(Results can be found in Liang YC. 3 ) Patients who could not be stratified according to the disease risk index model criteria and those who underwent autologous HSCT were excluded.We also excluded five patients for insufficient following up information.Finally, we followed up with 144 patients and assessed their QOL at 12, 18, 36, and 60 months post-transplantation, respectively.This study was approved by our hospital's ethics committee (IRB no.2017021), and all subjects provided written informed consent in accordance with the Declaration of Helsinki.

| The Functional Assessment of Cancer Therapy-Bone Marrow Transplant
We assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT), Simplified Chinese Version 4.0. 17,18This assessment includes five domains: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and BMT-specific concerns (BMTS).Participants rated their responses on a scale from 0 to 4 (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much).The scores from these five domains were combined to generate a total score, with reliability coefficients ranging from 0.86 to 0.89. 18an X and colleagues confirmed that FACT-BMT is a reliable measure of QOL for Chinese HSCT patients. 19Higher scores indicate better QOL.

| Clinical data collection
Data concerning baseline clinicopathological features, disease information, pre-HSCT disease status, HSCT type, conditioning regimens (busulfan and cyclophosphamide or others), platelet levels (measured upon patients' exit from the protective environment), neutrophil engraftment time, and overall survival (OS) outcomes were collected from each patient's medical records.This information was obtained from the HSCT follow-up team responsible for monitoring HSCT patients within the department of hematology.

| Statistical analysis
Numerical data with normal or skewed distributions were presented as x ± SD or median with interquartile ranges and compared using Student's t-test or the Mann-Whitney U-test.Categorical data were presented as numbers with percentages and compared using the chi-square test or Fisher exact method, as appropriate.A latent class mixed model was employed to divide patient groups based on PWB score dynamics.The Kaplan-Meier curve with the log-rank test was utilized for survival analysis.A multivariate Cox model was applied to estimate survival probabilities according to PWB class.Multiple imputation was used for missing value analysis.
For latent profile analysis, two different latent class growth models of PWB were estimated: the first fitting only one latent profile, the second two profile groups.Each model included terms for linear time effects according to the 8 time point design.The estimated latent profile group with the higher BIC was selected. 20Statistical analyzes were performed using the survival, survminer, and LCMM packages in R software (Version 4.0.3,Vienna, Austria).

| Patients' characteristics
A total of 144 patients were analyzed, 69 patients diagnosed AML, 42 patients were acute lymphocytic leukemia, 25 patients were MDS, 3 patients were lymphoma and 3 patients were chronic myeloid leukemia.Among all the patients, the 5-year OS was 65%, and the progression-free survival (PFS), non-relapse mortality (NRM), and graft-versus-host diseasefree (GRFS) rates were 48%, 17%, and 36%, respectively.Analysis all the survival patients after 5 years transplantation, there were 59.8% patients had already back to normal living status.The association of baseline clinical features with OS outcome was displayed in Table S1.

| Relationship between FACT-BMT and survival outcomes
No clinical covariates were found to be predictive of survival.

| Definition of two patient classes based on PWB score
A latent class mixed model was utilized to divide HSCT patients into two groups based on PWB scores throughout the 60-month follow-up period.Results revealed that the first class (Class 1) exhibited a lower PWB score during the initial 48 months post-HSCT, with a gradual increasing trend observed.In contrast, the second class (Class 2) maintained a slower PWB level increase throughout the follow-up period and showed a lower PWB compared to Class 2 after 48 months (Figure 1).Their baseline characteristics and information of transplantation are presented in Table 1.Most clinical characteristics were similar between PWB Class 1 and Class 2 patients.
F I G U R E 1 Two group latent class analysis of PWB trajectories through 60 months follow up.
T A B L E 1 Baseline demographic and medical data of the participants in the study.This retrospective study demonstrated the value of QOL parameters, especially the PWB in prediction of survival in long-term following up HSCT patients (Figure 3).
HSCT remains the only curative option for various malignant hematological disorders.However, the high economic costs and inherent risks associated with the procedure have limited its widespread application.Therefore, developing a robust risk assessment protocol for individuals undergoing HSCT is of utmost importance.While existing scoring systems like the HCT-CI and DRI have been proposed to assess HSCT risk, they primarily rely on objective parameters and may not fully capture patientreported data.In contrast, studies such as that conducted by William et al. have shown the crucial role of patientreported data in enhancing HSCT risk stratification. 9he evaluation of QOL in patients undergoing HSCT is crucial as it provides valuable insights into their physical and emotional well-being. 21,22In this study, we followed patient's QOL with FACT-BMT for 5 years, and we discovered that the quality-of-life score reached a nadir after allogeneic HSCT and gradually improved within 6 months post-HSCT.A higher QOL score over time was associated with improved survival at 5 years.
With the further analysis, we found that the trajectory of PWB over a five-year follow-up period closely mirrored the overall QOL trajectory.This observation aligns with previous research, 3,23 reaffirming the consistency of these findings in the field of HSCT.Our investigation into life quality evaluation revealed that HSCT patients commonly experienced physical discomfort, fatigue, nausea, pain, and sleepiness as their primary complaints.These symptoms  are consistent with the well-documented side effects associated with HSCT and its preparatory treatments. 24otably, we observed an improvement in QOL relative to the patients' pre-disease state by the 12-month follow-up, which is an encouraging finding.Despite the challenges and hardships faced during HSCT, many patients manage to regain a sense of normalcy and wellbeing over time.Moreover, our study sheds light on the timing of emotional recovery in HSCT patients.While some studies have reported a delayed improvement in emotional status occurring after HSCT, our results show that declining physical health was associated with psychological recovery.This correlation underscores the complex interplay between physical and emotional well-being in HSCT patients.Healthcare providers must recognize the importance of addressing both aspects of patients' health throughout the HSCT journey to optimize their overall QOL.
One of the most encouraging findings in our study is that most patients in our cohort were able to return to work and resume a normal lifestyle within 3-5 years after HSCT.This highlights the resilience and adaptability of HSCT patients, as well as the advancements in supportive care measures and post-transplant rehabilitation programs.The ability to regain a sense of normalcy in life is a critical indicator of successful transplantation and improved QOL.
Furthermore, our study reveals a significant correlation between early QOL trajectories following HSCT and OS.Patients who demonstrated better life quality trajectories in the early post-transplant period had improved OS rates.This observation emphasizes the importance of integrating QOL assessments into the routine care of HSCT patients as predictive indicators of long-term outcomes.This finding aligns with our previous research 3 and underscores the need to prioritize QOL as a critical outcome measure in HSCT.In our study, we utilized a state-of-the-art latent class model (LCA) to investigate the relationship between QOL and survival in HSCT patients.This advanced statistical approach allowed us to analyze high-dimensional data without relying solely on predefined outcomes.The benefits of LCA have been demonstrated in various medical contexts, including studies on acute respiratory distress syndrome (ARDS), where it successfully classified patients into distinct sub-phenotypes associated with survival outcomes.LCA-based PWB trajectories were found to be correlated with survival outcomes.][26] Additionally, exacerbations in physical conditions, coupled with emotional stress and limitations in self-care, may contribute to a vicious cycle that compromises longterm survival.This highlights the importance of early intervention and support for HSCT patients to break this cycle and improve their long-term prognosis. 27,28urthermore, our findings emphasize the need for a comprehensive risk assessment protocol for HSCT patients that incorporates patient-reported data.While existing scoring systems like HCT-CI and DRI have their merits, the inclusion of PROs can provide a more holistic understanding of a patient's condition and improve risk stratification.Leveraging advanced statistical methods such as LCAs can further enhance our ability to predict outcomes and tailor interventions to the specific needs of HSCT patients.
Additionally, our findings suggest that early monitoring of QOL in the post-HSCT period is crucial.Patients who exhibited more favorable QOL trajectories in the initial stages of their transplant journey had improved OS rates.This highlights the importance of early identification and intervention for patients who may be at risk of experiencing prolonged physical or emotional distress.Furthermore, integrating PROs into routine clinical assessments can improve patient-centered care, enhance communication between patients and healthcare providers, and enable personalized treatment approaches. 29espite the valuable insights provided by our study, there are several limitations that must be acknowledged.First, the QOL instrument used in our study was developed a century ago, and while it remains a valuable tool, it may lack some key elements relevant to modern society and the unique challenges faced by HSCT patients.This limitation highlights the need for continuous refinement and adaptation of QOL assessment tools to capture the evolving needs and experiences of patients.Second, the complexity of the numerous items in the QOL questionnaire may have made it less favorable for some patients to complete, leading to a high rate of missing data.Future research should focus on developing more concise and patient friendly QOL assessment tools to mitigate this issue.

| CONCLUSION
Early-stage PWB in HSCT patients may serve as a novel predictor of long-term survival.This finding highlights the importance of considering QOL assessments and addressing PWB early in the HSCT journey.Further studies are warranted to explore the potential role of life quality as an interventional target in HSCT patients and to develop a more comprehensive approach to patient care in this complex medical journey.

2
Note: BUCY regimen (including cytarabine, busulfan, and cyclophosphamide) for myeloablative conditioning for 7 days.Cytarabine (8 g/msq) used on Day 1 to Day 2 and was infused for 3 h/day; busulfan (9.6 mg/kg) used from Day 3 to Day 5 and was infused for 8 h/day (divided into four infusion periods a day of 2 h each); and cyclophosphamide (3.6 g/msq) used from Day 6 to Day 7 and was infused for 3 h/day.Unit of house incoming in China is Yuan.Most clinical characteristics were similar between PWB Class 1 and Class 2 patients, except for the transplantation type.Two patient classes based on physical well-being (PWB) score.

Total N = 144 Class 1 n = 27 Class 2 n = 117 X 2 p-value
Multivariate analysis of LCA class and overall survival in HSCT patients.Model 2, adjusted for sex, age, marriage, house incoming, source of hospitalization, Previous history, diagnose, type of HSCT, disease status before HSCT, complication before HSCT, complication in HSCT, induced program.c Model 3, adjusted for hematopoietic reconstitution, disease status before HSCT, complication before HSCT, complication before HSCT (eye infection), complication before HSCT (renal insufficiency), complication before HSCT (cardiac insufficiency), complication before HSCT (central nervous leukemia), complication before HSCT (abnormal liver function), induced program, grouped by HCT-CR.Study flow.
T A B L E 2 b